Skip to main content

Carboplatin with or without Nivolumab in Treating Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Trial Status: Active

This phase II trial studies how well carboplatin with or without nivolumab works in treating patients with triple-negative breast cancer that has spread to nearby tissues and lymph nodes or has spread to other places in the body and cannot be removed by surgery. Drugs used in chemotherapy, such as carboplatin and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with or without nivolumab may work better in treating patients with triple-negative breast cancer.

Inclusion Criteria

  • Participants must have histologically or cytologically confirmed invasive breast cancer, with unresectable locally advanced or metastatic disease; participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation
  • Estrogen-receptor and progesterone-receptor expression both =< 1% by immunohistochemistry (IHC), and HER2-negative status as determined by the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines; if a patient has more than one histological result, the most recent sample will be considered for inclusion
  • Participants must have PD-L1 status available at the time of registration; standard local testing with any PD-L1 antibody that has been validated in a Clinical Laboratory Improvement Act (CLIA)-certified environment will be acceptable for including patients on trial; primary or metastatic samples may be tested for PD-L1 status
  • Participants must have measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline; previously collected archival tissue will also be obtained on all participants; for participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or participant safety concern) the archival tissue alone will be acceptable; tissue needs to be located and availability confirmed at time of registration; participants must agree to a mandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible; for patients randomized to carboplatin alone who decide to crossover to nivolumab + nab-paclitaxel at time of progression, a mandatory biopsy will be required, if tumor is safely accessible, prior to initiating crossover treatment; participants must also agree to undergo this biopsy, if applicable
  • Participants must have received 0 prior chemotherapeutic regimens for metastatic breast cancer; prior platinum in the neo/adjuvant setting is permissible, if at least 6 months elapsed since the end of adjuvant systemic therapy to the development of metastatic disease; all toxicities related to prior chemotherapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 grade 1 or lower
  • Prior poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors are not allowed in the metastatic setting; prior PARP inhibitors in the neo/adjuvant setting are permissible, if at least 6 months elapsed since the end of adjuvant systemic therapy to the development of metastatic disease; all toxicities related to prior biologic therapy must have resolved to CTCAE v4.0 grade 1 or lower
  • Patients may have received prior radiation therapy; radiation therapy must be completed at least 7 days prior to registration, and all toxicities related to prior radiation therapy must have resolved to CTCAE v4.0 grade 1 or lower; patients may not have had > 25% of their bone marrow radiated
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky > 60%)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9.0 g/dl
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.0 x ULN in patients with documented Gilbert's syndrome)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN or =< 5 x institutional ULN for participants with documented liver metastases
  • Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 45 mL/min/ 1.73 m^2 for participants with creatinine levels above institutional ULN
  • Note: supportive care (e.g. transfusion of red blood cells) is allowed to meet eligibility criteria
  • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to registration * Childbearing potential is defined as: participants who have not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus)
  • Women of childbearing potential (WOCBP) must agree to use an adequate method of contraception; contraception is required starting with the first dose of study medication through 150 days (5 months) after the last dose of study medication; examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment (i.e., 90 days [duration of sperm turnover] plus the time required for the investigational drug to undergo approximately five half-lives)
  • Participants on bisphosphonates or receptor activator of nuclear factor kappa B (RANK) ligand inhibitors may continue receiving therapy during study treatment
  • The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document

Exclusion Criteria

  • Concurrent administration of any other anti-cancer therapy during the course of this study (bisphosphonates and RANK ligand inhibitors are allowed)
  • Prior hypersensitivity to platinum chemotherapy or to any of the excipients of platinum or nivolumab therapy
  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including pembrolizumab, ipilimumab, and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with a history of treated central nervous system (CNS) metastases are eligible; treated brain metastases are defined as those without ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or computed tomography [CT] scan) completed during screening; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 7 days prior to registration; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, surgery or a combination as deemed appropriate by the treating physician; radiation therapy must be completed at least 7 days prior to registration
  • Major surgery within 2 weeks prior to registration; patients must have recovered from any effects of any major surgery
  • Uncontrolled, significant intercurrent or recent illness including, but not limited to, ongoing or active infection, uncontrolled non-malignant systemic disease, uncontrolled seizures, or psychiatric illness/social situation that would limit compliance with study requirements in the opinion of the treating investigator
  • Participant has a medical condition that requires chronic systemic steroid therapy (> 10 mg of prednisone daily or equivalent) or any other form of immunosuppressive medication (including disease modifying agents) and has required such therapy in the last 2 years; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy
  • Participant has documented history of autoimmune disease or syndrome that currently requires systemic steroids or immunosuppressive agents
  • History or evidence of active, non-infectious pneumonitis or interstitial lung disease
  • Individuals with a history of a second malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers that have been diagnosed and treated within the past 3 years are eligible: cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer of the skin; patients with other cancers diagnosed within the past 3 years and felt to be at low risk of recurrence should be discussed with the study sponsor to determine eligibility
  • Participant is known to be positive for the human immunodeficiency virus (HIV), hepatitis B surface antigen (HepBsAg), or hepatitis C virus (HCV) RNA; HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions of combination antiretroviral therapy with study drugs; in addition, these participants are at increased risk of fatal infections when treated with marrow-suppressive therapy
  • The participant has received a live vaccine within 28 days prior to registration; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine; the use of the inactivated seasonal influenza vaccine is allowed
  • Women who are pregnant or breastfeeding or adults of reproductive potential not employing an adequate method of contraception * Childbearing potential is defined as: participants who have not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus)

Connecticut

Stamford
Stamford Hospital / Bennett Cancer Center
Status: ACTIVE
Contact: K.M. Steve Lo
Phone: 203-276-2695

Maine

Bangor
Eastern Maine Medical Center
Status: ACTIVE
Contact: Zarah Dulce F. Lucas

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Nadine Muskatel Tung
Phone: 617-667-7081
Brigham and Women's Hospital
Status: ACTIVE
Contact: Sara Michell Tolaney
Phone: 617-632-4209
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Sara Michell Tolaney
Phone: 617-632-4209
Brighton
Steward Saint Elizabeth's Medical Center
Status: ACTIVE
Contact: Dorcas Doja Chi
Milford
Dana-Farber / Brigham and Women's Cancer Center at Milford Regional
Status: ACTIVE
Contact: Natalie Sinclair
Phone: 508-488-3700
South Weymouth
Dana-Farber / Brigham and Women's Cancer Center at South Shore
Status: ACTIVE
Contact: Meredith Faggen
Worcester
UMass Memorial Medical Center-Hahnemann Campus
Status: ACTIVE
Contact: Madhavi K. Toke

New Hampshire

Londonderry
The Dana-Farber Cancer Institute at Londonderry
Status: ACTIVE
Contact: Frederick M. Briccetti
Phone: 603-552-9100

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Robert Wesolowski
Phone: 614-366-8541

Vermont

Burlington
University of Vermont Medical Center
Status: ACTIVE
Contact: Peter Andrew Kaufman

PRIMARY OBJECTIVE:

I. To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by progression-free survival (PFS), as first-line therapy in the metastatic setting for patients with unselected (by PD-L1 status) metastatic triple-negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (1) and immune-related response criteria (irRC) (2), in patients with unselected metastatic TNBC.

II. To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall survival (OS), in patients with unselected metastatic TNBC.

III. To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by clinical benefit rate (CBR) according to RECIST 1.1, in patients with unselected metastatic TNBC.

IV. To evaluate the duration of response (DOR) and time to objective response (TTOR) of carboplatin in combination with nivolumab versus carboplatin alone, in patients with unselected metastatic TNBC.

V. To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by PFS, ORR according to RECIST 1.1 and irRC, CBR, DOR, TTOR and OS, in patients with PD-L1-positive metastatic TNBC (defined as >= 1% of the tumor cell population demonstrating unequivocal staining for PD-L1).

VI. To explore the efficacy of carboplatin alone or in combination with nivolumab, in terms of PFS, ORR according to RECIST 1.1 and irRC, CBR, DOR, TTOR and OS, for metastatic TNBC in patients with germline BRCA1 or BRCA2 mutations.

VII. To explore the efficacy of nab-paclitaxel in combination with nivolumab, in terms of PFS, ORR according to RECIST 1.1 and irRC, CBR, DOR, TTOR and OS, as second-line therapy in patients with metastatic TNBC who crossover after progression on carboplatin alone, and explore outcomes by PD-L1 status.

VIII. To evaluate the safety and tolerability of carboplatin in combination with nivolumab, and compare to that of carboplatin alone, in patients with metastatic TNBC previously treated with 0 lines of chemotherapy in the metastatic setting.

IX. To evaluate the safety and tolerability of nab-paclitaxel in combination with nivolumab, as second-line therapy in patients with metastatic TNBC who crossover after progression on carboplatin alone.

CORRELATIVE OBJECTIVES:

I. To explore tissue biomarkers of antitumoral immune activity and tumor genomic instability as predictors of response, or resistance, to carboplatin plus nivolumab, compared to carboplatin alone, in patients with metastatic TNBC.

II. To characterize tumor-infiltrating lymphocytes (TILs), by histological assessment, at baseline and correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

III. To characterize the expression of markers of immune cell subsets (i.e. CD8 for cytotoxic T cells, CD68 for macrophages), inhibitory checkpoint pathway molecules (i.e. PD-1, PD-L1, TIM3, LAG3), and co-stimulatory pathway molecules (i.e. GITR, OX40) by immunohistochemistry (IHC) and/or immunofluorescence (IF).

IV. To explore whether immunosuppressive and/or immune-stimulating immune marker profiles at baseline correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

V. To characterize mutational load and neoantigen burden at baseline and correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, and OS).

VI. To characterize ribonucleic acid (RNA) expression signatures of immune pathway activation and deoxyribonucleic acid (DNA) damage repair deficiency at baseline and correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, and OS).

VII. To explore whether changes in TILs, immunosuppressive and/or immune-stimulating immune marker profiles, mutational load, neoantigen burden, and RNA expression signatures, between paired biopsies from baseline and after 2 cycles of treatment, correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

VIII. To explore mechanisms of resistance to carboplatin plus nivolumab, compared to carboplatin alone, in paired biopsies from baseline and at time of progression.

IX. To explore blood biomarkers of antitumoral immune activity as predictors of response, or resistance, to carboplatin plus nivolumab, compared to carboplatin alone, in patients with metastatic TNBC.

X. To characterize serial changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) and in plasma over the course of study treatment.

XI. To explore whether induction of changes in the immunosuppressive and/or immune-stimulating immune marker profile in PBMCs correlates with disease response to therapy (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

XII. To investigate whether there is an immune marker (i.e. PD-L1) in circulating PBMCs that correlates to tumor infiltrating lymphocyte (TIL) percentage in baseline tumor.

XIII. To characterize serial changes of neoantigen burden in circulating tumor DNA and correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

XIV. To explore serial changes in blood biomarkers as mechanisms of resistance to carboplatin plus nivolumab, compared to carboplatin alone.

XV. To explore the structure and function of the gut microbiome as predictors of response, or resistance, to carboplatin plus nivolumab, compared to carboplatin alone, in patients with metastatic TNBC.

XVI. To characterize structure and function of the gut microbiome at baseline and correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

XVII. To explore whether changes in the overall diversity of gut microbiome, estimated by Shannon index, correlate with disease response to treatment (PFS, objective response assessed by RECIST 1.1 and irRC, OS).

XVIII. To explore mechanisms of resistance to carboplatin plus nivolumab, compared to carboplatin alone, in paired samples from baseline and at time of progression.

XX. To explore correlations between diversity and taxa of the gut microbiome and 1) diet composition, 2) physical activity patterns, and 3) body mass index (BMI).

XXI. To explore tissue, blood and microbiome biomarkers as predictors of response, or resistance, to nab-paclitaxel plus nivolumab, in patients with metastatic TNBC who crossover after progression on carboplatin alone.

XXII. To explore the relationship between response to carboplatin plus nivolumab and diet composition, physical activity patterns and body mass index.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and carboplatin IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carboplatin IV over 30-60 minutes on day. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally receive nivolumab IV over 30 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 100 days and every 6-12 weeks or 6 months thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Sara Michell Tolaney

  • Primary ID 17-512
  • Secondary IDs NCI-2018-00269
  • Clinicaltrials.gov ID NCT03414684